The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [¹¹C]-(R)-3 ([¹¹C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [¹¹C]-(R)-3 readily crosses the blood–brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer’s disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [¹¹C]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human.

中文翻译：

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用于体外和体内神经影像学的全基因组选择性放射性标记的TrkB / C抑制剂：合成，临床前评价和人类首创

原癌基因NTRK1 / 2/3编码原肌球蛋白受体激酶TrkA / B / C，在神经生物学和癌症中起关键作用。我们在此描述[ ¹¹ C]-（R）-3（[ ¹¹ C]-（R）-IPMICF16）的发现，这是一流的正电子发射断层扫描（PET）TrkB / C靶向放射性标记的激酶抑制剂前导。依靠广泛的人类运动学审查，我们显示（R）-3是迄今表征的最有效和最具选择性的TrkB / C抑制剂。证明了[ ¹¹ C]-（R）-3恩替替尼阻断研究证明，它很容易穿过啮齿动物的血脑屏障（BBB）并在体内选择性结合TrkB / C受体。在体外观察到人脑组织中大量的TrkB / C特异性结合，与健康的大脑相比，阿尔茨海默氏病（AD）海马的特异性减少。我们还提供了有关灵长类动物中[ ¹¹ C]-（R）-3的大脑处置的初步翻译数据，包括首次人类评估。这些结果首次说明了全蛋白全范围选择性放射性化学探针在人体内内源性激酶PET神经成像中的应用。